Myeloid cells are the most abundant family of immune cells present in all tissues of our body. These cells are key regulators of the immune system, responsible for the linking of innate and adaptive immune responses. Among myeloid cells, monocytes present great properties for circulating in the blood to reach and infiltrate other tissues, where they are differentiated toward macrophages with better properties for phagocytosis, antigen presentation, and cytokine secretion, thus playing pivotal roles in immune surveillance and tissue homeostasis. Dysfunctions in the generation, differentiation, and/or polarization of monocytes/macrophages have been found in all immune-related diseases, including cancer. Therefore, their study has become key for the diagnosis and therapeutic management of these pathologies. The development of monocyte-based/macrophage-based cell therapies is a new field of research, which aims to take advantage of the intrinsic properties of these cells and to manipulate them using the most advanced biotechnological approaches for therapeutic purposes. Pharmacological intervention, genetic engineering, and even nanotechnological strategies are being implemented for the reprogramming of these cells, their use as delivery carriers, inserting chimeric antigen receptors (CARs), or other approaches. Thus, herein, we describe the nature of myeloid cells focusing on the origin, differentiation, and polarization of monocytes/macrophages in cancer- and immune-related diseases. And we provide a description of the preclinical and clinical studies presented in the last years for the manipulation of these innate immune cells with therapeutic purposes.